Menstrual-related migraine is a common form of migraine affecting >50% of female migraineurs. Acupuncture may be a choice for menstrual-related migraine, when pharmacological prophylaxis is not suitable. However, the efficacy of acupuncture has not been confirmed. We design and perform a randomized controlled clinical trial to evaluate the efficacy of acupuncture compared with naproxen in menstrual-related migraine patients.
This is a multicenter, single blind, randomized controlled clinical trial. A total of 184 participants will be randomly assigned to two different groups. Participants will receive verum acupuncture and placebo medicine in the treatment group, while participants in the control group will be treated with sham acupuncture and medicine (Naproxen Sustained Release Tablets). All treatments will be given for 3 months (menstrual cycles).
The primary outcome measures are the change of migraine days inside the menstrual cycle and the proportion of responders (defined as the proportion of patients with at least a 50% reduction in the number of menstrual migraine days). The secondary outcome measures are the change of migraine days outside the menstrual cycle, duration of migraine attack, the Visual Analogue Scale (VAS), and intake of acute medication. The assessment will be made at baseline (before treatment), 3 months (menstrual cycles), and 4 months (menstrual cycles) after the first acupuncture session.
The results of this trial will be helpful to supply the efficacy of acupuncture for menstrual-related migraine prophylaxis.
A new MRI technique to map the oxygenation of venous blood is presented. The method uses velocity-selective excitation and arterial nulling pulses, combined with phase sensitive signal detection to isolate the venous blood signal. The T2 of this signal along with a T2-Y calibration curve yields estimates of venous oxygenation in situ. Results from phantoms and healthy human subjects under normoxic and hypoxic conditions are shown, and venous saturation levels estimated from both sagittal sinus and grey matter based ROIs are compared to the related techniques TRUST and QUIXOTIC. In addition, combined with an additional scan without arterial nulling pulses, the oxygen saturation level on arterial side can also be estimated.
Venous Oxygen Saturation; Arterial Oxygen Saturation; Velocity Selective Excitation; T2; VSEAN; TRUST; QUIXOTIC; Magnetic Resonance Imaging
Cell adhesion, migration and invasion are critical steps for carcinogenesis and cancer metastasis. Ganoderma lucidum, also called Lingzhi in China, is a traditional Chinese medicine, which exhibits anti-proliferation, anti-inflammation and anti-metastasis properties. Herein, GAEE, G. lucidum extract mainly contains ganoderiol A (GA), dihydrogenated GA and GA isomer, was shown to inhibit the abilities of adhesion and migration, while have a slight influence on that of invasion in highly metastatic breast cancer MDA-MB-231 cells at non-toxic doses. Further investigation revealed that GAEE decreased the active forms of focal adhesion kinase (FAK) and disrupted the interaction between FAK and SRC, which lead to deactivating of paxillin. Moreover, GAEE treatment downregulated the expressions of RhoA, Rac1, and Cdc42, and decreased the interaction between neural Wiskott-Aldrich Syndrome protein (N-WASP) and Cdc42, which impair cell migration and actin assembly. To our knowledge, this is the first report to show that G.lucidum triterpenoids could suppress cell migration and adhesion through FAK-SRC-paxillin signaling pathway. Our study also suggests that GAEE may be a potential agent for treatment of breast cancer.
The aim of the present study was to evaluate the association of maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) with anthropometry in the offspring from birth to 12 months old in Tianjin, China.
Between 2009 and 2011, health care records of 38,539 pregnant women had been collected, and their children had been measured body weight and length at birth, 3, 6, 9 and 12 months of age. The independent and joint associations of pre-pregnancy BMI and GWG based on the Institute of Medicine (IOM) guidelines with anthropometry in the offspring were examined using General Linear Model and Logistic Regression.
Prepregnancy BMI and maternal GWG were positively associated with Z-scores for birth weight-for-gestational age, birth length-for-gestational age, and birth weight-for-length. Infants born to mothers with excessive GWG had the greatest changes in Z-scores for weight-for-age from birth to Month 3, and from Month 6 to Month 12, and the greatest changes in Z-scores for length-for-age from birth to months 3 and 12 compared with infants born to mothers with adequate GWG. Excessive GWG was associated with an increased risk of offspring overweight or obesity at 12 months old in all BMI categories except underweight.
Maternal prepregnancy overweight/obesity and excessive GWG were associated with greater weight gain and length gain of offspring in early infancy. Excessive GWG was associated with increased infancy overweight and obesity risk.
Xeroderma pigmentosum variant (XP-V) is a subtype of xeroderma pigmentosum (XP) disease with typical pigmentation and types of cancer in the oral maxillofacial and other sun-exposed regions. Few factors of tumor proneness in XP-V have been completely elucidated with the exception of the POLH [which encodes DNA polymerase η (pol η)] mutation. The aim of the present study was to identify the POLH mutation in an XP-V patient and to explore the roles of specific additional polymerases in XP-V tumor proneness. The POLH gene was sequenced in the patient and the expression of pol η, ι, κ, θ and ζ was tested in XP-V tumor cells and cell lines, as well as in HeLa cells with POLH knockdown. The results revealed a novel, large homozygous deletion of POLH (del exon 5–9) in the patient. Lower expression of pol κ, θ and ζ were observed in the XP-V cells and similar changes were observed in HeLa cells with POLH knockdown. Consistent with XP-V tumor cells, following UV irradiation, the expression of pol κ and θ presented was significantly increased in the XP-V cell lines compared with that in the normal control cells. The unusual expression of other polymerases, besides pol η, identified in the present study indicated that these polymerases may also be key in XP-V cells genetic instability, which accelerates tumor formation.
POLH; mutation; Xeroderma pigmentosum; XP-V
Avermectins produced by Streptomyces avermitilis are potent anti-parasitic agents that are useful in animal health care, agriculture, and the treatment of human infections. In a search for novel regulators that affect avermectin biosynthesis, comparative transcriptome analysis was performed between wild-type strain ATCC31267 and avermectin overproducing strain 76-02-e, revealing some differentially expressed genes. SAV576, which is downregulated in 76-02-e and encodes a TetR family transcriptional regulator (TFR), was shown to inhibit avermectin production by indirectly affecting the expression of ave genes. SAV576 directly repressed the transcription of its gene SAV576 and of adjacent genes SAV575 (encodes cytochrome P450/NADPH-ferrihemoprotein reductase) and SAV574. The SAV576-binding sites within the bidirectional SAV575-SAV576 promoter region were determined by DNase I footprinting assays. A consensus 15-bp palindromic sequence CCRTACRVYGTATGS was found in these binding sites and shown to be important for SAV576-binding activity. SAV575, an important target gene of SAV576, was shown to exert a positive effect on avermectin production. The study findings extend our limited knowledge of the complex regulation of avermectin biosynthesis and provide a basis for rational genetic manipulation of S. avermitilis to improve avermectin production through control of SAV576 and its target gene.
The loss of von Hippel–Lindau (VHL) protein function leads to highly vascular renal tumors characterized by an aggressive course of disease and refractoriness to chemotherapy and radiotherapy. Loss of VHL in renal tumors also differs from tumors of other organs in that the oncogenic cascade is mediated by an increase in the levels of hypoxia-inducible factor-2α (HIF2α) instead of hypoxia-inducible factor-1α (HIF1α).
Methods and Principal Findings
We used renal carcinoma cell lines that recapitulate the differences between mutant VHL and wild-type VHL genotypes. Utilizing a method relying on extracted peptide intensities as a label-free approach for quantitation by liquid chromatography–mass spectrometry, our proteomics study revealed regulation of key proteins important for cancer cell survival, proliferation and stress-resistance, and implicated differential regulation of signaling networks in VHL-mutant renal cell carcinoma. We also observed upregulation of cellular energy pathway enzymes and the stress-responsive mitochondrial 60-kDa heat shock protein. Finding reliance on glutaminolysis in VHL-mutant renal cell carcinoma was of particular significance, given the generally predominant dependence of tumors on glycolysis. The data have been deposited to the ProteomeXchange with identifier PXD000335.
Conclusions and Significance
Pathway analyses provided corroborative evidence for differential regulation of molecular and cellular functions influencing cancer energetics, metabolism and cell proliferation in renal cell carcinoma with distinct VHL genotype. Collectively, the differentially regulated proteome characterized by this study can potentially guide translational research specifically aimed at effective clinical interventions for advanced VHL-mutant, HIF2α-over-expressing tumors.
Objective. To investigate the relationship between Brachial-ankle pulse wave velocity (baPWV), and its associated risk factors in Chinese patients with RA.
Methods. 138 Chinese RA patients and 150 healthy subjects were included. baPWV of all the participants was measured. RA related factors were determined, as well as traditional cardiovascular risk factors.
Results. baPWV was significant higher in RA group (1705.44 ± 429.20 cm/s) compared to the healthy control group (1386.23 ± 411.09 cm/s) (P < 0.001). Compared with low baPWV group, high baPWV group patients were significantly older (P = 0.008) and taller (P = 0.033). Serum cholesterol (P = 0.035), triglycerides (P = 0.004), and LDL level (P = 0.006) were significantly higher in high baPWV group patients compared with low baPWV group patients. The baPWV of RA patients was positively correlated with age (r = 0.439, P < 0.001), and serum cholesterol level (r = 0.231, P = 0.035), serum triglycerides level (r = 0.293, P < 0.001), serum LDL level (r = 0.323, P = 0.003). Meanwhile, baPWV negatively correlated with the height of RA patients (r = −0.253, P = 0.043). Multivariate regression analysis showed that baPWV of RA group was independently associated with age and serum triglycerides level. Conclusions. The old age and high level of serum triglycerides may be the major determinants of arterial stiffness in Chinese RA patients.
fluorescence; label; oligonucleotide; multicolor; Real-time; tracking; imaging
Binding of HIV to the chemokine coreceptor CXCR4 mediates viral fusion and signal transduction that promotes actin dynamics critical for HIV infection of blood resting CD4 T cells. It has been suggested that this gp120-mediated actin activity resembles the chemotactic actin dynamics mediated by chemokines such as SDF-1. To determine whether inhibiting SDF-1-mediated chemotactic activity can also inhibit HIV infection, we screened several inhibitors known to reduce SDF-1-mediated chemotaxis of T cells.
We found that a tyrosine kinase inhibitor, genistein, inhibited both SDF-1-mediated chemotaxis and HIV infection of resting CD4 T cells. Genistein was also found to interfere with SDF-1- and HIV-mediated actin dynamics in CD4 T cells. This reduction in actin activity correlates with genistein-mediated inhibition of viral DNA accumulation in resting CD4 T cells. In addition, we also tested two other tyrosine kinase inhibitors, sunitinib and AG1478. Sunitinib, but not AG1478, inhibited HIV infection of resting CD4 T cells. We further tested the safety of genistein in 3 Chinese rhesus macaques (Macaca mulatta), and each animal was given a monotherapy of genistein at 10 mg/kg orally for 12 weeks. No adverse drug effects were observed in these animals.
Our results suggest that novel therapeutic strategies can be developed based on targeting cellular proteins involved in HIV-dependent signaling. This approach can interfere with HIV-mediated actin dynamics and inhibit HIV infection.
HIV-1; Actin; SDF-1; Genistein; Sunitinib; Cofilin; LIMK1
Diabetic patients, through incompletely understood mechanisms, endure exacerbated ischemic heart injury compared to non-diabetic patients. Intermedin (IMD) is a novel calcitonin gene-related peptide (CGRP) superfamily member with established cardiovascular protective effects. However, whether IMD protects against diabetic myocardial ischemia/reperfusion (MI/R) injury is unknown.
Diabetes was induced by streptozotocin in Sprague–Dawley rats. Animals were subjected to MI via left circumflex artery ligation for 30 minutes followed by 2 hours R. IMD was administered formally 10 minutes before R. Outcome measures included left ventricular function, oxidative stress, cellular death, infarct size, and inflammation.
IMD levels were significantly decreased in diabetic rats compared to control animals. After MI/R, diabetic rats manifested elevated intermedin levels, both in plasma (64.95 ± 4.84 pmol/L, p < 0.05) and myocardial tissue (9.8 ± 0.60 pmol/L, p < 0.01) compared to pre-MI control values (43.62 ± 3.47 pmol/L and 4.4 ± 0.41). IMD administration to diabetic rats subjected to MI/R decreased oxidative stress product generation, apoptosis, infarct size, and inflammatory cytokine release (p < 0.05 or p < 0.01).
By reducing oxidative stress, inflammation, and apoptosis, IMD may represent a promising novel therapeutic target mitigating diabetic ischemic heart injury.
Intermedin; Ischemia-reperfusion; Diabetes; Oxidative stress; Apoptosis; Inflammatory
Oxidized bases in DNA have been implicated in cancer, aging and neurodegenerative disease. We have developed an approach combining single-cell gel electrophoresis (comet) with fluorescence in situ hybridization (FISH) that enables the comparative quantification of low, physiologically relevant levels of DNA lesions in the respective strands of defined nucleotide sequences and in the genome overall. We have synthesized single-stranded probes targeting the termini of DNA segments of interest using a polymerase chain reaction-based method. These probes facilitate detection of damage at the single-molecule level, as the lesions are converted to DNA strand breaks by lesion-specific endonucleases or glycosylases. To validate our method, we have documented transcription-coupled repair of cyclobutane pyrimidine dimers in the ataxia telangiectasia-mutated (ATM) gene in human fibroblasts irradiated with 254 nm ultraviolet at 0.1 J/m2, a dose ∼100-fold lower than those typically used. The high specificity and sensitivity of our approach revealed that 7,8-dihydro-8-oxoguanine (8-oxoG) at an incidence of approximately three lesions per megabase is preferentially repaired in the transcribed strand of the ATM gene. We have also demonstrated that the hOGG1, XPA, CSB and UVSSA proteins, as well as actively elongating RNA polymerase II, are required for this process, suggesting cross-talk between DNA repair pathways.
Recent studies have suggested that a functional cure for HIV-1 infection, purportedly resultant from allogeneic bone marrow transplantation, may be possible. Additionally, the first such patient was treated with whole-body irradiation, immunosuppressants, and the chemotherapeutic, cytarabine. However, the precise role of the coinciding medical interventions in diminishing detectable HIV reservoirs remains unstudied.
In this article, we demonstrate that the immunosuppressants, mycophenolic acid and cyclosporine, and the chemotherapeutic, cytarabine, are potent antiretroviral agents at clinically relevant dosages. These drugs strongly inhibit HIV-1 replication in a GFP indicator T cell line and peripheral blood mononuclear cells (PBMC).
Our study suggests that certain clinical immunosuppressants and chemotherapeutic agents may act combinatorially to inhibit HIV infection. Additionally, chemotherapy-mediated cytotoxicity may also affect the stability of viral reservoirs. Thus, further study is needed to examine potential therapeutic value of these interventions in patients.
HIV-1; Rev-CEM; CD4 T cells; Chemotherapy; Mycophenolic acid; Cyclosporine; Cytarabine
Protein nitration has been recognized as an important biomarker for nitroxidative stress associated with various diseases. While identification of protein targets for nitration is important, its quantitative profiling also is necessary to understand the biological impact of this low-abundance posttranslational modification. We have previously reported an efficient and straightforward enrichment method for nitropeptides to reduce sample complexity and permit unambiguous site-specific identifications by LC–MS analyses. This approach relies on two chemical derivatization steps: specifically reductive methylation of aliphatic amines and, then, conversion of nitrotyrosines to the corresponding aminotyrosines before their selective capture by a solid-phase reagent we introduced previously. Hence, the method inherently offers the opportunity for relative quantitation of nitropeptides by using isotopic variants of formaldehyde for reductive methylation. This simple method was tested via LC–MS analyses of differently N-methylated nitropeptides and nitroubiquitin as a model nitroprotein enriched from human serum albumin digest and from human plasma, respectively.
Protein nitration; Stable-isotope labeling; Enrichment; Relative quantitation; LC–MS; Tandem mass spectrometry
AIM: To investigate different methods of creating incomplete intestinal obstruction in a rat model and to compare their electrophysiologic, morphologic and histologic characteristics.
METHODS: Rat ileum was partially obstructed by the respective application of: braided silk (penetrated the mesentery and surrounded intestine); half ligation (penetrated directly and ligated 1/2 cross-section of the intestine); wide pipe (6 mm in width, surrounded the intestine); narrow pipe (2 mm in width, surrounded the intestine). A control was also included (no obstruction). Various behavioral and electrophysiologic variables, as well as morphologic and immunohistochemical observations were recorded by blinded investigators at different time points (12, 24, 48, 72 h), including daily general condition, ileal wet weight and circumference, macromorphous and micromorphous intestine, bowel movement capability in vivo and in vitro, slow wave and neural electrical activity, and the number of c-Kit positive interstitial cells of Cajal (ICC).
RESULTS: Despite being of a similar general condition, these methods resulted in different levels of obstruction in each group compared with the control at different time points (12, 24, 48, 72 h). However, these fields of the wide pipe rat showed significantly differences when compared with the other three obstructed groups at 12 to 72 h, including macroscopic and histological presentation, intestinal transit ratio and contractility, circumference and wet weight, amplitude and frequency of nerve electrical discharge and slow wave, and ICC numbers (all P < 0.01).
CONCLUSION: The wide pipe rat method is significantly more reliable and stable than the other methods of obstruction, demonstrating that use of the wide pipe method can be a useful model of incomplete intestinal obstruction.
Intestinal obstruction; Model; Comparative study; Electrophysiology; Morphology; Interstitial cells of Cajal
Previous studies suggest that there may be a distinct relationship between spontaneous neural activity and subsequent or concurrent self-specific stimulus-induced activity. This study aims to test the impact of spontaneous activity as recorded in an eyes-open (EO) resting state as opposed to eyes-closed (EC) on self-specific versus non-self-specific auditory stimulus-induced activity in fMRI. In our first experiment we used self-specific stimuli comprised of the subject’s own name and non-self-specific stimuli comprised of a friend’s name and an unknown name, presented during EO versus EC baselines in a 3 name condition × 2 baseline design. In Experiment 2 we directly measured spontaneous activity in the absence of stimuli during EO versus EC to confirm a modulatory effect of the two baseline conditions in the regions found to show an interaction effect in Experiment 1. Spontaneous activity during EO was significantly higher than during EC in bilateral auditory cortex and non-self-specific names yielded stronger signal changes relative to EO baseline than to EC. In contrast, there was no difference in response to self-specific names relative to EO baseline than to EC despite the difference between spontaneous activity levels. These results support an impact of spontaneous activity on stimulus-induced activity, moreover an impact that depends on the high-level stimulus characteristic of self-specificity.
eyes-open; eyes-closed; resting state; self; spontaneous activity; intrinsic activity; rest-stimulus interaction; self-specific stimulus
Posttranslational carbonylation of proteins by the covalent attachment of the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) is a biomarker of oxidative stress. Tandem mass spectrometry (MS/MS) has become an essential tool for characterization of this modification. Chemical tagging methods have been used to facilitate the immunoaffinity-based enrichment or even quantification of HNE-modified peptides and proteins. With MS/MS spectra of the untagged modified peptides considered as references, a comparative evaluation is presented focusing on the impact of affinity-tagging with four carbonyl-specific reagents (2,4-dinitrophenyl hydrazine, biotin hydrazide, biotinamidohexanoic acid hydrazide and N’-aminooxymethylcarbonylhydrazino D-biotin) on collision-induced dissociation of the tagged HNE-carbonylated peptides. Our study has shown that chemical labeling may not be carried out successfully for all the peptides and with all the reagents. The attachment of a tag usually cannot circumvent the occurrence of strong neutral losses observed with untagged species and, in addition, fragmentation of the introduced tag may also be introduced. Chemical tagging of certain peptides may, nevertheless, afford more sequence ions upon MS/MS than the untagged carbonylated peptide, especially when Michael addition of the lipid peroxidation product occurs on cysteine residues. Therefore, tagging may increase the confidence of identifications of HNE-modified peptides by database searches.
Protein carbonylation has been associated with various pathophysiological processes. A representative reactive carbonyl species (RCS), 4-hydroxy-2-nonenal (HNE), has been implicated specifically as a causative factor for the initiation and/or progression of various diseases. To date, however, little is known about the proteins and their modification sites susceptible to “carbonyl stress” by this RCS, especially in the liver. Using chemoprecipitation based on a solid phase hydrazine chemistry coupled with LC-MS/MS bottom-up approach and database searching, we identified several protein-HNE adducts in isolated rat liver mitochondria upon HNE exposure. The identification of selected major protein targets, such as the ATP synthase β-subunit, was further confirmed by immunoblotting and a gel-based approach in combination with LC–MS/MS. A network was also created based on the identified protein targets that showed that the main protein interactions were associated with cell death, tumor morphology and drug metabolism, implicating the toxic nature of HNE in the liver mitoproteome. The functional consequence of carbonylation was illustrated by its detrimental impact on the activity of ATP synthase, a representative major mitochondrial protein target for HNE modifications.
Latent HIV reservoirs are the primary hurdle to eradication of infection. Identification of agents, pathways and molecular mechanisms that activate latent provirus may, in the presence of highly active antiretroviral therapy, permit clearance of infected cells by the immune system. Promoter-proximal pausing of RNA polymerase (Pol) II is a major rate-limiting step in HIV gene expression. The viral Tat protein recruits human Super Elongation Complex (SEC) to paused Pol II to overcome this limitation. Here, we identify the bromodomain protein Brd4 and its inhibition of Tat-transactivation as a major impediment to latency reactivation. Brd4 competitively blocks the Tat–SEC interaction on HIV promoter. The BET bromodomain inhibitor JQ1 dissociates Brd4 from the HIV promoter to allow Tat recruitment of SEC to stimulate HIV elongation. JQ1 synergizes with another latency activator prostratin, which promotes Pol II loading onto the viral promoter. Because JQ1 activates viral latency without inducing global T cell activation, this and other closely related compounds and their antagonization of Brd4 to promote Tat–SEC interaction merit further investigations as effective agents/strategies for eliminating latent HIV.
Furanodiene (FUR) is a natural terpenoid isolated from Curcumae Rhizoma, a well-known Chinese medicinal herb that presents antiproliferation activities in several cancer cell lines. In this study, we demonstrated that FUR concentration dependently inhibits the cell proliferation of A549, NIH-H1299, and 95-D lung cancer cells. β-elemene, another terpenoid isolated from Curcumae Rhizoma, exhibited weaker antiproliferative effects in A549 and NIH-H1299 cells and activities similar to FUR in 95-D cells. FUR significantly inhibited colony formation in A549 and 95-D cells and upregulated both the mRNA and protein expression levels of binding immunoglobulin protein (BIP) and C/EBP homologous protein (CHOP), indicating that endoplasmic reticulum (ER) stress is induced. FUR treatment led to the accumulation of CHOP in the nucleus, which further confirms induction of ER stress. Furthermore, combined treatment of FUR with paclitaxel showed significant synergetic activities in NIH-H1299 and 95-D cells, suggesting its potential roles in combination therapy. These findings provide a basis for the further study of the anticancer effects in vivo and the internal mechanisms of FUR.
Chemokine binding to cognate receptors induces actin dynamics that are a major driving force for T cell migration and chemotactic motility. HIV-1 binding to the chemokine coreceptor CXCR4 initiates chemotactic signaling, mimicking chemokine-induced actin dynamics to facilitate infection processes such as entry, early DNA synthesis, and nuclear migration. Recently, we identified that HIV-triggered early actin polymerization is mediated through the Rac1-PAK1/2-LIMK1-cofilin pathway. Inhibition of LIMK1 (LIM domain kinase 1), a kinase phosphorylating cofilin, through shRNA knockdown decreases actin polymerization and T cell chemotaxis toward SDF-1. The LIMK1 knockdown T cells also supported lower viral entry, DNA synthesis and nuclear migration, suggesting a critical role of LIMK1-mediated actin dynamics in the initiation of HIV-1 infection. Surprisingly, LIMK1 knockdown in CEM-SS T cells did not lead to an overall change in the ratio of phospho-cofilin to total cofilin although there was a measurable decrease in the amount of actin filaments in cells. The decrease in filamentous actin in LIMK1 knockdown cells was found to mainly occur in polarized cap region rich in F-actin. These results suggest that LIMK1 may be involved in spontaneous actin polarization in transformed T cells. The inhibition of T cell chemotaxis by LIMK1 knockdown likely result from inhibition of localized LIMK1 activation and cofilin phosphorylation that are required for polarized actin polymerization for directional cell migration. The inhibition of HIV-1 infection by LIMK1 knockdown may also result from the decrease of actin-rich membrane protrusions that may be preferred viral entry sites in T cells.
LIMK1; cofilin; chemotaxis; SDF-1; CXCR4; HIV-1; CD4 T cells; Rac1; Pak1; Pak2
Anti-obesity drugs are widely used to prevent the complications of obesity, however, the effects of anti-obesity drugs on cardiovascular risk factors are unclear at the present time. We carried out a comprehensively systematic review and meta-analysis to assess the effects of anti-obesity drugs on cardiovascular risk factors.
Methodology and Principal Findings
We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles and proceedings of major meetings for relevant literatures. We included randomized placebo-controlled trials that reported the effects of anti-obesity drugs on cardiovascular risk factors compared to placebo. Overall, orlistat produced a reduction of 2.39 kg (95%CI-3.34 to −1.45) for weight, a reduction of 0.27 mmol/L (95%CI: −0.36 to −0.17) for total cholesterol, a reduction of 0.21 mmol/L (95%CI: −0.30 to −0.12) for LDL, a reduction of 0.12 mmol/L (95%CI: −0.20 to −0.04) for fasting glucose, 1.85 mmHg reduction (95%CI: −3.30 to −0.40) for SBP, and a reduction of 1.49 mmHg (95%CI: −2.39 to −0.58) for DBP. Sibutramine only showed effects on weight loss and triglycerides reduction with statistical significances. Rimonabant was associated with statistically significant effects on weight loss, SBP reduction and DBP reduction. No other significantly different effects were identified between anti-obesity therapy and placebo.
We identified that anti-obesity therapy was associated with a decrease of weight regardless of the type of the drug. Orlistat and rimonabant could lead to an improvement on cardiovascular risk factors. However, Sibutramine may have a direct effect on cardiovascular risk factors.
Rationale: The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The transcription factor Yin Yang 1 (YY1) plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known.
Objectives: To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis.
Methods: Lung fibroblasts were cultured with transforming growth factor (TGF)-β or tumor necrosis factor-α. Nuclear factor (NF)-κB, YY1, and α-smooth muscle actin (SMA) were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial YY1-deficient mouse and a YY1f/f conditional knockout mouse after being exposed to silica or bleomycin.
Measurements and Main Results: TGF-β and tumor necrosis factor-α up-regulated YY1 expression in lung fibroblasts. TGF-β–induced YY1 expression was dramatically decreased by an inhibitor of NF-κB, which blocked I-κB degradation. YY1 is significantly overexpressed in both human IPF and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that YY1 can up-regulate α-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1+/−) mice were significantly protected from lung fibrosis, which was associated with attenuated α-SMA and collagen expression. Finally, decreasing YY1 expression through instilled adenovirus-cre in floxed-YY1f/f mice reduced lung fibrosis.
Conclusions: YY1 is overexpressed in fibroblasts in both human IPF and murine models in a NF-κB–dependent manner, and YY1 regulates fibrogenesis at least in part by increasing α-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for pulmonary fibrosis.
nuclear factor-κB; α-smooth muscle actin; idiopathic pulmonary fibrosis
For an infecting viral pathogen, the actin cortex inside the host cell is the first line of intracellular components that it encounters. Viruses devise various strategies to actively engage or circumvent the actin structure. In this regard, the human immunodeficiency virus-1 (HIV-1) exemplifies command of cellular processes to take control of actin dynamics for the initiation of infection. It has becomes increasingly evident that cortical actin presents itself both as a barrier to viral intracellular migration and as a necessary cofactor that the virus must actively engage, particularly, in the infection of resting CD4 blood T cells, the primary targets of HIV-1. The coercion of this most fundamental cellular component permits infection by facilitating entry, reverse transcription, and nuclear migration, three essential processes for the establishment of viral infection and latency in blood T cells. It is the purpose of this review to examine, in detail, the manifestation of viral dependence on the actin cytoskeleton, and present a model of how HIV utilizes actin dynamics to initiate infection.
HIV-1; gp120; Nef; Actin; Cofilin; LIMK1; Arp2/3; CD4; CXCR4; Chemokine; Chemotaxis